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Localizing Antifungal Drugs to the Correct Organelle Can Markedly Enhance their Efficacy
Author(s) -
Benhamou Raphael I.,
Bibi Maayan,
Berman Judith,
Fridman Micha
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201802509
Subject(s) - organelle , antifungal drug , endoplasmic reticulum , drug , azole , antifungal , biology , antifungal drugs , drug development , cell , drug target , microbiology and biotechnology , computational biology , chemistry , pharmacology , biochemistry
Abstract A critical aspect of drug design is optimal target inhibition by specifically delivering the drug molecule not only to the target tissue or cell but also to its therapeutically active site within the cell. This study demonstrates, as a proof of principle, that drug efficacy can be increased considerably by a structural modification that targets it to the relevant organelle. Specifically, by varying the fluorescent dye segment an antifungal azole was directed from the fungal cell mitochondria to the endoplasmic reticulum (ER), the organelle that harbors the drug target. The ER‐localized azole displayed up to two orders of magnitude improved antifungal activity and also dramatically reduced the growth of drug‐tolerant fungal subpopulations in a panel of Candida species, which are the most prevalent causes of serious human fungal infections. The principle underlying the “target organelle localization” approach provides a new paradigm to improve drug potency and replenish the limited pipeline of antifungal drugs.